Prediction of methotrexate elimination after high dose infusion in children with acute lymphoblastic leukaemia using a population pharmacokinetic approach.

ABSTRACT

High-dose methotrexate (HD-MTX) with leucovorin rescue is a component of therapy in children with acute lymphoblastic leukaemia. Since MTX toxicity is related to drug exposure, a monitoring of serum MTX concentrations at H24, H48, H72 and until the concentration is less than 0.2 micromol/L is commonly performed. However, a number of patients may reach concentrations of less than 0.2 micromol/L long before the next sampling is scheduled. The aim of our study was to develop a Bayesian method predicting the time at which MTX concentration reaches 0.2 micromol/L in order to decrease the number of samples drawn and to allow for a more rapid patient discharge. Methotrexate population parameters were estimated from a retrospective analysis of 60 infusions in 23 children and MTX concentrations were predicted from an independent set of 20 courses in 14 children with a Bayesian approach using either one (H48) or two (H24 and H48) samples. The following population parameters were obtained using a two-compartment model CL = 3.51 L/h (inter-individual variability 66%), Vd = 8.67 L (58%), k12 = 0.0044 h(-1)(105%), k21 = 0.039 h(-1)(25%). Clearance and Vd were found to increase with weight and age respectively. Both sampling schedules tested for the Bayesian estimation enabled accurate prediction of concentrations and provided satisfactory precision despite a small bias. When considering the ability to predict the time at which the threshold was reached, the one-sample (H48) schedule gave the best results. We conclude that a sampling schedule involving only one sample and Bayesian parameter estimation may be able to predict the delay necessary to reach 0.2 micromol/L in each individual.